(1) Field of the Invention
The present invention generally relates to genes and proteins that affect diseases in mammals. More specifically, the invention is directed to methods for determining the likelihood that a subject will develop Alzheimer's disease. The invention is also directed to proteins that affect Ca2+ transport in cells.
(2) Description of the Related Art
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by a massive brain loss and by the presence of senile plaques and neurofibrillary tangles, two characteristic cerebral lesions formed by the aggregation of Aβ and tau proteins, respectively (Mattson, 2004; Selkoe, 2001). Sequential proteolysis of the amyloid-beta precursor protein (APP) by beta- and gamma-secretases produces two major Aβ species, Aβ40 and Aβ42, and increased Aβ production could represent a key determinant in amyloid formation and thus in the pathogenesis of AD.
The first atrophy observed in the AD brain occurs in the medial temporal lobe, which includes the hippocampus, and is the result of a massive synaptic degeneration and neuronal death (Braak and Braak, 1991). This early neurodegenerative process in the hippocampus is believed to lead to the characteristic learning and memory impairments observed in AD patients (de Leon et al., 2004). The etiology of the disease is complex because of its strong genetic heterogeneity (Marambaud and Robakis, 2005). Rare autosomal dominant mutations in the genes coding for the amyloid precursor protein (APP) and presenilins cause early-onset AD, whereas complex interactions between different genetic variants are believed to modulate the risk for the vast majority of late onset AD (LOAD) cases (Kennedy et al., 2003; Pastor and Goate, 2004). Concordant evidence of linkage to LOAD has been observed in different chromosomal regions, including on chromosome 10 where strong susceptibility loci are present (Kehoe et al., 1999; Bertram et al., 2000; Myers et al., 2000; Ertekin-Taner et al., 2000; Blaker et al., 2003; Farrer et al., 2003). Although significant associations with several candidate genes have been reported within these regions, the only susceptibility gene unambiguously demonstrated worldwide is the ε4 allele of APOE on chromosome 19 (Strittmatter et al., 1993). However, epidemiological studies indicate that the inheritance of the APOE ε4 allele cannot explain the overall heritability of AD, implying that a significant proportion of LOAD cases is attributable to additional genetic risk factors (Pastor and Goate, 2004).